1. Field of the Invention
The present invention relates to pharmaceutical agents (compounds) which act as leukotriene B4 (LTB.sub.4) synthesis inhibitors in mammals. The compounds inhibit LTB4 synthesis by inhibiting phospholipase A2 (PLA.sub.2) activity. PLA.sub.2 is an important enzyme in the biosynthesis of leukotrienes as PLA.sub.2 acts to release arachidonic acid from phospholipids. Once released, arachidonic acid is rapidly metabolized by a variety of enzymes of the arachidonic acid cascade to produce prostaglandins, leukotrienes and related compounds. The use of the compounds herein to inhibit PLA.sub.2 activity thus inhibits the release of arachidonic acid from phospholipids. The inhibition of release of arachidonic acid similarly diminishes subsequent products in the arachidonic acid cascade, such as prostaglandins, leukotrienes, and related compounds, including LTB.sub.4.
LTB.sub.4 is an arachidonic acid metabolite which is produced by the 5-lipoxygenase pathway. Pharmacologically, LTB.sub.4 is an important mediator of inflammation. LTB.sub.4 is known to induce chemotaxis, chemokinesis, aggregation, and degranulation of leukocytes in vitro, and to induce accumulation of polymorphonuclear leukocytes, and increase vascular permeability and edema formation in vivo. Particularly high levels of LTB.sub.4 are detected in lesions in inflammatory diseases such as rheumatoid or spondylarthritis, gout, psoriasis, ulcerative colitis, Crohn's disease, multiple sclerosis and some respiratory diseases. Since the compounds herein inhibit PLA.sub.2 and thereby LTB.sub.4 synthesis, the compounds of the present invention are useful in treating inflammatory conditions in mammals such as rheumatoid arthritis, inflammatory bowel disease, psoriasis and the like.
Accordingly, it is an object of this invention to produce compounds for use as pharmaceutical agents which will exhibit LTB.sub.4 inhibitory activity in mammals More specifically to produce compounds which inhibit LTB.sub.4 activity by acting as inhibitors of PLA.sub.2 enzymes.
The pharmacology of the biologically active leukotrienes is generally discussed in J. Clin. Invest. 73, 889-897 (1984).